4′-C-substituted-2-haloadenosine derivative

a derivative and c-substitute technology, applied in the field of 4′csubstituted2haloadenosine derivatives, can solve the problems of not being able to achieve the effects of d4t, halogen atoms remain unknown, and the selectivity index cannot be improved, so as to achieve enhanced anti-hiv activity, anti-hiv activity is higher, and the effect of antiviral activity

Active Publication Date: 2008-03-04
YAMASA SHOYU CO LTD
View PDF6 Cites 46 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The present inventors have performed studies on the anti-HIV activity, etc. of the newly synthesized derivatives, and have found that 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine—which is obtained by introducing a fluorine atom to the 2-position of the base moiety of 2′-deoxy-4′-C-ethynyladenosine (i.e., lead compound)—exhibits resistance to inactivation by adenosine deaminase, has potent antiviral activity against a multi-drug-resistant virus strain exhibiting resistance to various anti-HIV drugs such as AZT, ddI, ddC, d4T, and 3TC, and exhibits enhanced anti-HIV activity and considerably lowered cytotoxicity.
[0017]As shown in the Test Examples provided hereinbelow, the compounds of the present invention (e.g., 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine) exhibit resistance to inactivation by adenosine deaminase, have potent antiviral activity against a multi-drug-resistant virus strain exhibiting resistance to various anti-HIV drugs such as AZT, ddI, ddC, d4T, and 3TC, exhibit unexpectedly enhanced anti-HIV activity; specifically, anti-HIV activity higher by a factor of 144 than that of 2′-deoxy-4′-C-ethynyladenosine (i.e., lead compound), and exhibit considerably lowered cytotoxicity. Therefore, surprisingly, the compounds of the present invention exhibit a selectivity index of 110,000, which is considerably higher than that of 2′-deoxy-4′-C-ethynyladenosine (EdAdo) (i.e., 1,630).
[0018]As described above, the compounds of the present invention exhibit excellent anti-HIV activity, particularly against a multi-drug-resistant HIV strain having resistance to various anti-HIV drugs such as AZT, DDI, DDC, D4T, and 3TC, exhibit less cytotoxicity, and exhibit resistance to inactivation by adenosine deaminase. Therefore, the compounds of the present invention are envisaged for development for producing pharmaceuticals, particularly drugs for treating AIDS.

Problems solved by technology

However, whether or not selectivity index can be improved through introduction of a halogen atom has remained unknown.
However, effects similar to those of d4T are not expected to be obtained in an adenosine derivative, which is a purine nucleoside, whose basic skeleton differs considerably from that of d4T, and therefore, this literature does not provide useful information for the present inventors' purposes.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 4′-C-substituted-2-haloadenosine derivative
  • 4′-C-substituted-2-haloadenosine derivative
  • 4′-C-substituted-2-haloadenosine derivative

Examples

Experimental program
Comparison scheme
Effect test

synthesis example 1

Synthesis of 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (Compound 4)

(1) Synthesis of 9-(3,5-di-O-acetyl-2-deoxy-4-C-ethynyl-β-D-ribo-pentofuranosyl)-2,6-diaminopurine (Compound 2)

[0126]

[0127]Compound 1 (0.33 g, 1.14 mmol) was suspended in acetonitrile (10.0 ml), and acetic anhydride (0.23 ml, 2.43 mmol), triethylamine (0.67 g, 4.81 mmol), and a small amount of 4-dimethylaminopyridine were added to the resultant suspension, followed by stirring at room temperature overnight.

[0128]The thus-precipitated crystals were filtered and dried, to thereby yield compound 2 (0.40 g, 1.07 mmol, 93.9%).

[0129]1H-NMR(DMSO-d6)δ7.94(1H, s, H-8), 6.76(2H, bs, NH2), 6.27(1H, t, H-1′, J=7.00), 5.84(2H, bs, NH2), 5.60(1H, dd, H-3′, J=4.00, 6.80), 4.46(1H, d, H-5′a, J=11.5), 4.21(1H, d, H-5′b, J=11.5), 3.74(1H, s, ethynyl) 3.12(1H, m, H-2′a), 2.52(1H, m, H-2′b), 2.12, 2.03(each 3H, s, acetyl)

(2) Synthesis of 3′, 5′-di-O-acetyl-2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (Compound 3)

[0130]

[0131]Compound 2 (450 mg,...

synthesis example 2

Synthesis of 4′-C-cyano-2′-deoxy-2-fluoroadenosine (Compound 8)

(1) Synthesis of 9-(3,5-di-O-acetyl-4-C-cyano-2-deoxy-β-D-ribo-pentofuranosyl)-2,6-diaminopurine (Compound 6)

[0136]

[0137]Compound 5 (122 mg, 0.418 mmol) was suspended in acetonitrile (5.00 ml), and acetic anhydride (118 μl, 1.25 mmol), triethylamine (352 μl, 2.51 mmol), and a small amount of 4-dimethylaminopyridine were added to the resultant suspension, followed by stirring at room temperature overnight. The thus-precipitated crystals were filtered and dried, to thereby yield compound 6 (128 mg, 0.341 mmol, 81.6%).

[0138]1H-NMR(CDCl3) δ7.54(1H, s, H-8), 6.31(1H, t, H-1′, J=7.00), 6.06(1H, dd, H-3′, J=5.00, 6.50), 5.31(2H, bs, NH2), 4.95(1H, d, H-5′a, J=11.5), 4.80(2H, bs, NH2), 4.37(1H, d, H-5′b, J=12.0), 3.43(1H, m, H-2′a), 2.63(1H, m, H-2′b), 2.23, 2.12(each 3H, s, acetyl).

(2) Synthesis of 3′, 5′-di-O-acetyl-4′-C-cyano-2′-deoxy-2-fluoroadenosine (Compound 7)

[0139]

[0140]Compound 6 (118 mg, 0.314 mmol) was dissolved in 7...

synthesis example 3

Synthesis of 2-chloro-2′-deoxy-4′-C-ethynyladenosine (Compound 9)

[0145]

[0146]Benzyltriethylammonium nitrite (1.04 g, 4.36 mmol) was dissolved in dichloromethane (24.0 ml), and acetyl chloride (0.40 ml, 5.63 mmol) was added to the resultant solution, followed by stirring at 0° C. for 30 minutes. To the resultant solution, a solution of compound 2 (340 mg, 0.91 mmol) in dichloromethane (6.00 ml) was added, and the resultant mixture was stirred at 0° C. for three hours. The resultant reaction mixture was diluted with chloroform, and subsequently the resultant organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the resultant residue, 28% aqueous ammonia (10.0 ml) and methanol (15.0 ml) were added, and the resultant mixture was stirred at room temperature overnight. Thereafter, the resultant reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by means of silica gel column chr...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
Login to view more

Abstract

The present invention provides a 4′-C-substituted-2-haloadenosine derivative represented by the following formula [I], [II], or [III]:(wherein X represents a halogen atom, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen, a phosphate residue, or a phosphate derivative residue). The present invention also provides a pharmaceutical composition containing the derivative and a pharmaceutically acceptable carrier therefor. Such derivative is useful as medicine for the treatment of Acquired Immune Deficiency Syndrome (AIDS).

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates to 4′-C-substituted-2-haloadenosine derivatives and use thereof as a medicine, in particular a medicine which is useful for the treatment of acquired immunodeficiency syndrome (AIDS).[0003]2. Background Art[0004]The clinical setting for AIDS has been dramatically changed by a multi-drug combination therapy, which is sometimes called highly active antiretroviral therapy, or HAART. In HAART, nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and lamivudine (3TC), and protease inhibitors (PIs) are employed in combination.[0005]Although HAART has drastically decreased the number of deaths caused by AIDS, there has emerged a multi-drug resistant HIV-1 (human immunodeficiency virus-1) mutant exhibiting cross-resistance to various drugs. For example, in the early 1990s patients infected with an HIV exhibiting resistan...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(United States)
IPC IPC(8): C07H19/173C07H19/20A61K31/70C07H19/16
CPCC07H19/16A61P31/18A61P37/00A61P43/00
Inventor KOHGO, SATORUOHRUI, HIROSHIKODAMA, EIICHIMATSUOKA, MASAOMITSUYA, HIROAKI
Owner YAMASA SHOYU CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap